Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK
Year: 2016
Type: article
Abstract: No effective targeted therapies exist for cancers with somatic KRAS mutations. Here we develop a synthetic lethal chemical screen in isogenic KRAS-mutant and wild-type cells to identify clinical drug pairs. Our results show that dual inhibition of polo-like kinase 1 and RhoA/Rho kinase (ROCK) leads to the synergistic effects in KRAS-mutant cancers. Microarray analysis reveals that this combinatory inhibition significantly increases transcription and activity of cyclin-dependent kinase inhibitor p21(WAF1/CIP1), leading to specific G2/M phase blockade in KRAS-mutant cells. Overexpression of p21(WAF1/CIP1), either by cDNA transfection or clinical drugs, preferentially impairs the growth of KRAS-mutant cells, suggesting a druggable synthetic lethal interaction between KRAS and p21(WAF1/CIP1). Co-administration of BI-2536 and fasudil either in the LSL-KRAS(G12D) mouse model or in a patient tumour explant mouse model of KRAS-mutant lung cancer suppresses tumour growth and significantly prolongs mouse survival, suggesting a strong synergy in vivo and a potential avenue for therapeutic treatment of KRAS-mutant cancers.
Source: Nature Communications
DOI: 10.1038/ncomms11363
Institutions: Shanghai Medical College of Fudan University, Fudan University, Fudan University Shanghai Cancer Center, East China Normal University, Sichuan University, State Key Laboratory of Biotherapy, Vanderbilt University Medical Center, The University of Texas MD Anderson Cancer Center, Texas A&M University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W2396833496